Reduction of blood pressure by store‐operated calcium channel blockers

Abstract

The voltage‐operated Ca2+ channels (VOCC), which allow Ca2+ influx from the extracellular space, are inhibited by anti‐hypertensive agents such as verapamil and nifedipine. The Ca2+ entering from outside into the cell triggers Ca2+ release from the sarcoplasmic reticulum (SR) stores. To refill the depleted Ca2+ stores in the SR, another type of Ca2+ channels in the cell membrane, known as store‐operated Ca2+ channels (SOCC), are activated. These SOCCs are verapamil and nifedipine resistant, but are SKF 96465 (SK) and gadolinium (Gd3+) sensitive. Both SK and Gd3+ have been shown to reduce [Ca2+]i in the smooth muscle, but their effects on blood pressure have not been reported. Our results demonstrated that both SK and Gd3+ produced a dose‐dependent reduction in blood pressure in rat. The combination of SK and verapamil produced an additive action in lowering the blood pressure. Furthermore, SK, but not Gd3+ suppressed proliferation of vascular smooth muscle cells in the absence or presence of lysophosphatidic acid (LPA). SK decreased the elevation of [Ca2+]i induced by LPA, endothelin‐1 (ET‐1) and angiotensin II (Ang II), but did not affect the norepinephrine (NE)‐evoked increase in [Ca2+]i. On the other hand, Gd3+ inhibited the LPA and Ang II induced change in [Ca2+]i, but had no effect on the ET‐1 and NE induced increase in [Ca2+]i. The combination of verapamil and SK abolished the LPA‐ or adenosine‐5′‐triphosphate (ATP)‐induced [Ca2+]i augmentation. These results suggest that SOCC inhibitors, like VOCC blocker, may serve as promising drugs for the treatment of hypertension.

Induced Pluripotent Stem Cell–Derived Podocyte-Like Cells as Models for Assessing Mechanisms Underlying Heritable Disease Phenotype: Initial Studies Using Two Alport Syndrome Patient Lines Indicate Impaired Potassium Channel Activity

“…We then tested two other ligands known to activate the calciumsensing receptor: gadolinium (Brown et al, 1993) and spermidine (Quinn et al, 1997). Gadolinium was ineffective across all cell lines tested; however, this lack of effect should be viewed with caution since Gd 31 has been shown to suppress receptoractivated TRP and ORAI [calcium release-activated calcium channel protein 1 (Malasics et al, 2010;Bouron et al, 2015;Xu et al, 2015)] activity. In contrast, the polyamine spermidine was an effective modulator of [Ca 21 ] i .…”

STIM‐1 and ORAI‐1 channel mediate angiotensin‐II‐induced expression of Egr‐1 in vascular smooth muscle cells

“…Our data obtained using 2‐APB suggest that Egr‐1 induction may be among the molecular events that underlie the importance of IP 3 R in increased agonist‐mediated vascular resistance in hypertension. 2‐APB has been largely considered as a direct SOCE inhibitor (Peppiatt et al, ) and pharmacological inhibition of SOCE using SKF 96465 was recently shown to exert positive effects on blood pressure reduction, Ang‐II‐induced [Ca 2+ ] i release and LPA‐induced VSMC proliferation (Xu, Elimban, & Dhalla, ). Thus, our data demonstrating that 2‐APB decreases Ang‐II‐induced Egr‐1 expression suggest that Egr‐1 downregulation may be one of the mechanism by which SOCE blockers exert their vasculoprotective effects.…”

Increased caveolin‐1 expression enhances the receptor‐operated Ca2+ entry in the aorta of two‐kidney, one‐clip hypertensive rats

“…Endothelin‐1 (ET‐1) induces constriction in the vascular smooth muscle through two types of Ca 2+ ‐permeable non‐selective cation channels (ROCCs and SOCCs) (Ansari, Kaddour‐Djebbar, &Abdel‐Latif, ; Jiao et al., ; Kawanabe, Hashimoto, & Masaki, ). Endothelin‐1 can activate receptor‐operated Ca 2+ entry (ROCE) by activating phospholipase C expression to produce diacylglycerol (Kato et al., ), which subsequently stimulates the depletion of Ca 2+ stores in the sarcoplasmic reticulum, leading to activation of store‐operated Ca 2+ entry (SOCE) (Xu, Elimban, & Dhalla, ). Previous studies have suggested that ET‐1‐induced pulmonary arterial contraction is increased in pulmonary hypertension (Jiao et al., ; Liu et al., ; Wang et al., ).…”